Is CSMD2 p.Leu2247Pro (c.6740T>C) pathogenic?

CSMD2 p.Leu2247Pro (c.6740T>C) is classified Uncertain significance in CSMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.8845); Absent from gnomAD v4.1.

How common is CSMD2 p.Leu2247Pro (c.6740T>C) in the general population?

CSMD2 p.Leu2247Pro (c.6740T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CSMD2 p.Leu2247Pro (c.6740T>C)?

AlphaMissense predicts likely pathogenic (score 0.8845) — an in-silico prediction, not a clinical call.

CSMD2 p.Leu2247Pro

c.6740T>C · VCV4235074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8845 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.8845	likely pathogenic
REVEL	0.605	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 38 kb · p 0.2 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L2249P vs ClinVar L2247P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CSMD2
Protein: p.Leu2247Pro
Coding: c.6740T>C
MANE Select: NM_001281956
Type: single nucleotide variant
Location: chr1:33600981 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Residue 2247: the cub 13 domain

Full CSMD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSMD2 p.Pro1506= Likely benign ★★ same type
CSMD2 p.Ser3015= Benign ★★ same type
CSMD2 c.404+2T>A Uncertain significance ★ same type
CSMD2 c.6344-398G>T Uncertain significance ★ same type
CSMD2 c.6344-422A>G Uncertain significance ★ same type
CSMD2 c.6344-423T>C Uncertain significance ★ same type
CSMD2 c.6344-429G>A Uncertain significance ★ same type
CSMD2 c.6344-435G>A Uncertain significance ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/csmd2-p-leu2247pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown